Prediction of differentially expressed microRNAs in blood as potential biomarkers for Alzheimer’s disease by meta-analysis and adaptive boosting ensemble learning

Abstract

Background: Blood circulating microRNAs that are specific for Alzheimer’s disease (AD) can be identified from differentially expressed microRNAs (DEmiRNAs). However, non-reproducible and inconsistent reports of DEmiRNAs hinder biomarker development. The most reliable DEmiRNAs can be identified by meta-analysis. To enrich the pool of DEmiRNAs for potential AD biomarkers, we used a machine learning method called adaptive boosting for miRNA disease association (ABMDA) to identify eligible candidates that share similar characteristics with the DEmiRNAs identified from meta-analysis. This study aimed to identify blood circulating DEmiRNAs as potential AD biomarkers by augmenting meta-analysis with the ABMDA ensemble learning method. Methods: Studies on DEmiRNAs and their dysregulation states were corroborated with one another by meta-analysis based on a random-effects model. DEmiRNAs identified by meta-analysis were collected as positive examples of miRNA–AD pairs for ABMDA ensemble learning. ABMDA identified similar DEmiRNAs according to a set of predefined criteria. The biological significance of all resulting DEmiRNAs was determined by their target genes according to pathway enrichment analyses. The target genes common to both meta-analysis- and ABMDA-identified DEmiRNAs were collected to construct a network to investigate their biological functions. Results: A systematic database search found 7841 studies for an extensive meta-analysis, covering 54 independent comparisons of 47 differential miRNA expression studies, and identified 18 reliable DEmiRNAs. ABMDA ensemble learning was conducted based on the meta-analysis results and the Human MicroRNA Disease Database, which identified 10 additional AD-related DEmiRNAs. These 28 DEmiRNAs and their dysregulated pathways were related to neuroinflammation. The dysregulated pathway related to neuronal cell cycle re-entry (CCR) was the only statistically significant pathway of the ABMDA-identified DEmiRNAs. In the biological network constructed from 1865 common target genes of the identified DEmiRNAs, the multiple core ubiquitin-proteasome system, that is involved in neuroinflammation and CCR, was highly connected. Conclusion: This study identified 28 DEmiRNAs as potential AD biomarkers in blood, by meta-analysis and ABMDA ensemble learning in tandem. The DEmiRNAs identified by meta-analysis and ABMDA were significantly related to neuroinflammation, and the ABMDA-identified DEmiRNAs were related to neuronal CCR.